Chan and Ciufolini
(5 × 100 mL). The combined extracts were then washed with sat.
aq. NaHCO3 (2 × 50 mL) and brine (50 mL), dried (Na2SO4), and
concentrated to afford analytically pure 16 (3.87 g, 88%) as an
3-Methyl-4-[(3,4-dimethoxy-2-phenylmethoxy)phenyl]-6-[(5,6,8-
trimethoxy)-2-quolinyl]-(1H)-2-pyridinone, 42. A solution of
enone 41 (1.54, 2.98 mmol) and 2-cyanopropanamide (34, 300 mg,
3.00 mmol) in DMSO (75 mL) was degassed for 20 min (bubbled
through with argon) prior to the addition of potassium tert-butoxide
(670 mg, 6.00 mmol). The reaction was then stirred at RT for 5
min and at 100 °C for 5 h. After cooling to RT, 1 M HCl (100
mL) was then added dropwise (CAUTION! evolution of highly toxic
HCN gas), and the resulting mixture was extracted with EtOAc (5
× 50 mL). The combined organic extracts were washed with brine
(3 × 30 mL), dried (Na2SO4), and concentrated in vacuo. Flash
chromatography of the residue (100% EtOAc then MeOH:DCM,
1:9) afforded 42 (1.02 g, 60%) as a yellow solid; mp 92.5-95 °C.
1H: δ 10.80 (s, br, 1H), 8.38 (d, 1H, J ) 8.92), 7.70 (d, 1H, J )
8.99), 7.05-7.15 (m, 5H), 6.90 (s, 1H), 6.89 (d, 1H, J ) 8.40),
6.78 (d, 1H, J ) 8.58), 6.69 (s, 1H), 4.93 (s, 2H), 4.11 (s, 3H),
4.05 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 2.02 (s, 3H).
13C: δ 163.5, 154.1, 153.2, 149.8, 149.7, 147.5, 145.1, 143.1, 137.6,
137.1, 135.6, 134.6, 131.2, 130.1, 128.6, 128.4, 128.2, 127.1, 124.5,
124.3, 117.6, 108.1, 107.8, 99.4, 75.8, 61.7, 61.4, 57.3, 56.4, 56.3,
14.6. IR: 1642, 1610. ESI-MS: 569.1 [M + H]+. HRMS: Calcd
for C33H33N2O7 [M + H]+ ) 569.2288, found 569.2285. EA: Calcd
C 69.70%, H 5.67%, N 4.93%; found C 69.34%, H 5.85%, N
5.18%.
1
orange crystalline solid; mp 193.5-195 °C. H: δ 8.20 (s, 1H),
6.93 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 4.02 (s, 3H), 3.87 (s, 3H).
13C: δ 166.0, 154.8, 154.2, 144.7, 141.3, 137.0, 136.7, 125.6, 124.6,
99.7, 62.9, 57.9, 57.4, 54.1. IR: 1704. ESI-MS: 334.1 [M(35Cl)
+ Na]+, 336.1 [M(37Cl) + Na]+. HRMS: Calcd for C14H1435ClNO5
[M + Na]+ ) 334.0458, found 334.0459. EA: Calcd C 53.9%, H
4.53%, N 4.49%; found C 54.28%, H 4.86%, N 4.57%.
5,6,8-Trimethoxyquinoline-2-carboxylic Acid, Methyl Ester,
12. A mixture of 16 (636 mg, 2.04 mmol), 10% Pd-C (120 mg,
0.113 mmol), Et3N (1.0 mL, 7.2 mmol) in EtOAc (50 mL) was
stirred under a H2 atmosphere at RT for 45 min; then it was filtered
over Celite and concentrated to afford pure 12 (567 mg, quant.) as
an orange crystalline solid; mp 164-165.5 °C. 1H: δ 8.47 (d, 1H,
J ) 8.76), 8.15 (d, 1H, J ) 8.76), 6.84 (s, 1H), 4.04 (s, 3H), 4.01
(s, 3H), 3.99 (s, 3H), 3.89 (s, 3H). 13C: δ 167.0, 154.4, 151.6,
145.5, 135.8, 135.5, 132.0, 126.8, 122.7, 99.2, 62.4, 57.9, 57.2,
53.9. IR: 1708. ESI-MS: 278.1 [M + H]+, 300.1 [M + Na]+.
HRMS: Calcd for C14H15NO5 [M + H]+ ) 278.1028, found
278.1034. EA: Calcd C 60.64%, H 5.45%, N 5.05%; found C
60.80%, H 5.66%, N 5.09%.
1-[(5,6,8-Trimethoxy)-2-quinolinyl]-ethanone, 40. A suspen-
sion of 12 (7.00 g, 25.3 mmol) and NaH (60% in oil, 2.5 g, 62.5
mmol) in EtOAc (100 mL) and toluene (350 mL) was stirred at
110 °C for 15 h (CAUTION! vigorous evolution of highly
flammable H2 gas). The reaction was then cooled to RT and diluted
with sat. aq. NH4Cl (100 mL; CAUTION!). The aqueous phase was
acidified to pH 4 with 1 M HCl and extracted with EtOAc (3 ×
50 mL). The combined organic phases were washed with brine
(50 mL), dried (Na2SO4) and concentrated in vacuo. The residue
was then dissolved in 1,4-dioxane (150 mL; CAUTION! cancer
suspect agent). Aqueous 1 N HCl (100 mL) was added, and the
mixture was heated at 70 °C for 15 h. The solution was
concentrated, the wet residue was neutralized (sat. aq. NaHCO3),
and the mixture was extracted with EtOAc (3 × 100 mL). The
combined extracts were washed with sat. aq. NaHCO3 (50 mL)
and brine (50 mL), dried (Na2SO4) and concentrated. Flash
chromatography (EtOAc:hexanes:DCM, 1:3:1) of the residue af-
forded 40 (5.17 g, 78% over 2 steps): yellow solid; mp 144-145
°C. 1H: δ 8.48 (d, 1H, J ) 8.82), 8.13 (d, 1H, J ) 8.78), 6.91 (s,
1H), 4.13 (s, 3H), 4.06 (s, 3H), 3.93 (s, 3H), 2.87 (s, 3H). 13C: δ
200.6, 153.8, 150.8, 150.7, 135.7, 134.6, 130.9, 126.3, 119.0, 99.3,
61.7, 57.2, 57.0, 25.6. IR: 1690. ESI-MS: 284.1 [M + Na]+, 545
2-[5,6,8-Trimethoxy-2-quinolinyl]-4-[3,4-dimethoxy-2-(phe-
nylmethoxy)phenyl]-6-methoxy-5-methyl-3-iodopyridine, 44. A
mixture of 42 (1.48 g, 2.61 mmol) and potassium carbonate (2.15
g, 15.6 mmol) in DMF (110 mL) was stirred at RT for 5 min. Iodine
monochloride (2.11 g, 13.1 mmol) was then added, and the resulting
mixture was stirred in the dark at RT for 16 h. The reaction was
then diluted with sat. aq. NH4Cl (150 mL) and extracted with EtOAc
(4 × 75 mL). The combined organic extracts were washed with
sat. aq. Na2S2O3 (75 mL) and brine (75 mL), dried (Na2SO4), and
concentrated to give the sensitive iodopyridone. The crude iodopy-
ridone (1.27 g, 1.83 mmol) was immediately dissolved in benzene
(55 mL) and treated with Ag2CO3 (0.505 g, 1.83 mmol) and benzyl
bromide (0.450 mL, 3.66 mmol). The resulting mixture was stirred
in the dark for 3 days; then it was filtered through a bed of Celite
and concentrated. Purification by flash chromatography (EtOAc :
hexanes, 1:3) afforded 44 (520 mg, 36% over 2 steps) as a pale-
yellow foam. 1H: δ 8.46 (d, 1H, J ) 8.68), 7.62 (d, 1H, J ) 8.63),
7.26-7.46 (m, 5H), 7.03-7.22 (m, 5H), 6.90 (s, 1H), 6.77-6.79
(m, 2H, AB system), 5.43 (m, 2H, AB system), 5.06 (m, 2H, AB
system), 4.07 (s, 3H), 4.04 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.90
(s, 3H), 2.04 (s, 3H). 13C: δ 161.4, 157.3, 154.7, 154.1, 153.9,
153.5, 150.0, 149.0, 142.9, 138.3, 138.0, 135.9, 134.8, 130.5, 130.2,
128.6, 128.3, 128.0, 127.8, 127.7, 127.5, 124.5, 124.1, 123.0, 121.9,
107.7, 99.4, 91.6, 77.4, 75.0, 68.1, 61.7, 61.3, 57.5, 56.9, 56.2, 14.6.
IR: 2937, 1601, 1496, 1099. ESI-MS: 785.1 [M + H]+. HRMS:
Calcd for C40H37N2O7I [M + H]+ ) 785.1724, found 785.1727.
EA: Calcd C 61.23%, H 4.75%, N 3.57%; found C 61.47%, H
4.96%, N 3.65%.
2-[5,6,8-Trimethoxy-2-quinolinyl]-4-[3,4-dimethoxy-2-(phe-
nylmethoxy)phenyl]-6-methoxy-5-methyl-3-(N-phenylmethoxy-
carbonyl)pyridinamine, 46. A solution of 44 (222 mg, 0.283
mmol) in THF (2 mL) was added dropwise to a cold (-78 °C)
solution of n-butyllithium (0.354 mL of 1.6 M solution in hexanes,
0.566 mmol) in THF (30 mL). Bone dry CO2 gas was immediately
bubbled through the solution for 10 min at -78 °C and at RT for
20 min. The reaction was then quenched with water (2 × 30 mL)
and extracted with EtOAc (30 mL). The aqueous phase was further
acidified to pH 2 by addition of 1 M HCl and extracted with EtOAc
(2 × 30 mL). The combined organic extracts were washed with
brine (30 mL), dried (Na2SO4), and concentrated. The crude residue
was filtered through a bed of silica gel (washed with EtOAc:
hexanes, 1:1; eluted with MeOH:DCM, 5:95) to afford a yellow
paste (134 mg). A solution of this material plus diphenyl phosphoryl
azide (0.26 g, 0.21 mL, 0.96 mmol) and Et3N (0.70 mL, 5.0 mmol)
in benzene (40 mL) was refluxed for 15 h; then it was cooled to
[2M + Na]+. HRMS: Calcd for C14H15NO4 [M + Na]+
)
284.0899, found 284.0903. EA: Calcd C 64.36%, H 5.79%, N
5.36%; found C 64.52%, H 5.86%, N 5.54%.
(E)-3-[(3,4-Dimethoxy-2-phenylmetoxy)phenyl]-1-[(5,6,8-tri-
methoxy) -2-quinolyl]-2-propen-1-one, 41. To a solution of 40
(156 mg, 0.597 mmol) in EtOH (25 mL) was added dropwise a
solution of NaOH (1 g, 25 mmol) in water (5 mL). The mixture
was then stirred for 5 min at RT. A solution of the 2-benzyloxy-
3,4-dimethoxybenzaldehyde (120 mg, 0.657 mmol) in EtOH (2 mL)
was then added. After 15 h of stirring at RT, the reaction was diluted
with water (100 mL) and extracted with EtOAc (3 × 50 mL). The
combined organic extracts were washed with brine (2 × 50 mL),
dried (MgSO4), and concentrated. Flash chromatography of the
residue (EtOAc:hexanes, 1:2) afforded 41 (256 mg, 83%) as a
yellow foam. 1H: δ 8.53 (d, 1H, J ) 8.78), 8.32 (m, 2H,
overlapping resonances), 8.28 (d, 1H, J ) 8.68), 7.64 (d, 1H, J )
8.82), 7.52 (m, 2H, overlapping resonances), 7.26-7.35 (m, 3H),
6.91 (s, 1H), 6.78 (d, 1H, J ) 8.85), 5.14 (s, 2H), 4.11 (s, 3H),
4.08 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H). 13C: δ 189.6,
155.9, 153.8, 152.9, 151.7, 150.7, 142.8, 139.7, 137.3, 135.7, 134.5,
131.0, 128.9, 128.6, 128.3, 126.1, 123.6, 123.4, 120.5, 120.3, 108.0,
99.0, 76.4, 61.8, 61.3, 57.2, 56.8, 56.3. IR: 1661. ESI-MS: 516.1
[M + H]+. HRMS: Calcd for C30H29NO7 [M + Na]+ ) 538.1842,
found 538.1857.
8494 J. Org. Chem., Vol. 72, No. 22, 2007